Methods of producing intraocular lenses

ABSTRACT

Methods of producing an intraocular lens include introducing a solution into a lens forming enclosure, wherein the solution comprises discrete crosslinkable units of a size small enough to provide an optically clear solution while contributing to a high refractive index of at least 1.3, performing crosslinking between the units of the solution, and thereby forming a solid lens in the enclosure, optionally under a forming pressure.

FIELD OF INVENTION

[0001] The present invention relates to the field of intraocular lenses(IOLs) and in particular to new lens materials as well as to methods ofproducing accommodating lenses based on these materials in vivo, whichmeans that the lens is formed in the capsular bag of the eye.

BACKGROUND OF THE INVENTION

[0002] When an ophthalmic surgeon operates on a cataract (s)he replacesthe defective natural lens with a small artificial lens, an IOL. Inorder to remove the natural, cataractous lens, as well as to prepare forthe introduction of the IOL, an incision must be made into the eye. Formany years most of the IOLs were made of poly(methylmethacrylate), amaterial with good optical characteristics and compatibility withtissues in the eye. A disadvantage of PMMA is, however, that it is avery rigid material and the incision must be made big enough, at least5-6 mm, for implantation of the lens. With improved devices for removalof the natural lens by phacoemulsification, requiring only a rathersmall incision, there was a need for lenses with deformable optics. Thisintended property can be achieved, for instance, by making lenses whichare foldable or can be dried to a reduced size, but which swells to itsoriginal shape in the eye. Various silicone or hydrogel based lenseshave been suggested and in some cases also commercialized. In such smallincision surgery an opening of only 3-4 mm is required.

[0003] The implantation of lenses of the types mentioned abovenecessitates the patient using spectacle correction for reading. Morerecently, to overcome this limitation of the conventional IOL,increasing attention has been given to refractive, as well asdiffractive, bifocal or multifocal lenses. The use of such lenses isincreasing slowly, but as they introduce an optical deficiency inpatients, a reduced perception of contrast, which becomes more acute intwilight, their widespread application may be limited.

[0004] Even with the mentioned types of improved implantable IOLs,available on the market, there is still a desire to obtain a lens forwhich is required an even smaller incision and which behaves like thenatural lens in the eye, i.e. to be accommodating, with a focal pointwhich is regulated by action of the ciliary muscle in the eye. In orderto allow for a really small incision it would be necessary to form thelens inside the eye from a solution which is injected into the capsularbag or into a balloon placed inside the bag. Lenses formed from aninjected solution of monomers have already been suggested in theliterature and are based on a technique in which the natural lens isremoved and, after cleaning of the capsular bag, a polymerizablecomposition is injected into the bag, whereupon the solution ispolymerized, e.g. after initiation by light of suitable wavelength,using the form of the capsular bag as the mold. Thin walled inflatableballoons of silicone rubber have also been developed which can beinserted into the capsular bag and filled with the desired polymersystem.

[0005] Most researchers of the development of the accommodative re-filllens have used silicone based systems for filling the capsular bag,either in the form of silicone oils or low temperature vulcanizing (LTV)silicone elastomers. Such systems suffer from disadvantages in thecontext of re-fill lens formation: the dimethyl silicones have arestricted refractive index (1.40), LTVs cure slowly, up to 12 hours maybe needed to complete their setting and their slow setting may result inmaterial leakage out of the capsular bag through the surgical incision.In order to overcome this problem, U.S. Pat. No. 4,542,542 disclosessuch a silicon based injected system which is partially cured by heat inthe vicinity of the injection hole of the capsular bag to effect a firstsealing effect. It is a further complication that the high viscositiesof some silicone oils and intermediates make their air-bubble freeinjection very difficult.

[0006] Hettlich et al (German J Ophthalmol (1992) 1 p. 346-349) wereamong the first to propose the use of photopolymerization of a monomersystem as an alternative approach to setting the material within thecapsular bag. He pointed to the clinical success of blue lightphotocurable resins for dental applications and explored the use of suchsystems as injectible materials for filling capsular bags. The systemsused by Hettlich et al. were effective in demonstrating the efficacy ofblue light photocurable resins for filling capsular bags. Anotherexample of an injectible system is described in EP 414219, in which theliquid composition comprises a difunctional acrylate and/or methacrylateester and a photoinitiator activatable by light of wavelength 400-500nm. By choosing an initiator of such high wavelength the presence of aUV absorber, which is desired to be present in the final lens in orderto protect the retina from damage, does not create a problem.

[0007] Unfortunately, the in vivo polymerizable systems described so fardo not solve all the problems involved with this interesting andpotentially very useful concept, as e.g. leakage of monomers andinitiator from the bag into the surrounding parts of the eye betweeninjection and polymerization might occur. With increasing polymerizationtime such leakage might be substantial and cause serious complications.Another disadvantage observed in systems of the type described above isshrinkage of the material during polymerization with the formation of alens which does not completely fill up the capsular bag. Further, thesystems used have formed materials with moduli too high to allowaccommodative processes. The natural lens of the eye is a material withextremely low modulus, in the general range 1-5 kPa, which can becompared to glassy plastics with a modulus of six orders of magnitudegreater. PMMA as mentioned above has a value around 3000 MPa.

[0008] It would consequently be highly desirable to be able to obtain anophthalmically acceptable solution which could be injected into thecapsular bag of the eye with a conventional cannula after the naturallens has been surgically removed and that such a solution could besubjected to a process that would result in the production of anintraocular lens capable of functionally replace the natural lens, whileavoiding the above-mentioned problems. In particular, such a solutionmust be water based and in a simple manner capable of being reacted intoa gel formed solid lens material. It has earlier been described in U.S.Pat. No. 5,665,840 how to produce contact lenses from a water solublecrosslinkable pre-polymer. The production involves a photoinitiatorwhich is activated by UV-light to produce crosslinking reaction to thegel formed lens material. In this publication it is not considered howto inject a water based solution into the capsular bag for lensproduction and arrive with a lens of a suitable modulus.

[0009] It is obvious that several technical problems remain before amethod of producing an intraocular lens from injecting a water basedaqueous solution directly into the capsular bag can be accomplished in asufficiently safe and reproductive manner. As earlier mentioned, itwould be preferable to start from a material that is already polymerizedin order to avoid free monomers, although an aqueous solution ofsufficiently low viscosity to be injected through standard syringeequipment must be used for the purpose of minimizing the incision of thecapsular bag.

[0010] It is also a requirement that the material should have a suitablyhigh refractive index to generate a lens with sufficient optic power andquality and the material shall be able to be cured in a controlledmanner by visible light to a lens product with sufficiently lowelasticity (modulus) resembling that of the natural lens. Consequently,it is a further requirement to involve a photoinitiator, capable ofinducing a curing reaction of the material in aqueous solution which issubstantially free from clinical hazards.

[0011] The present invention aims to solve the mentioned problems byproviding novel methods of producing intraocular lenses and an aqueoussolution serving as an injectible starting material for the production.

DESCRIPTION OF THE INVENTION

[0012] The present invention refers to a method of producing anintraocular lens wherein a solution is introduced into a lens formingenclosure. The solution comprises discrete crosslinkable units of a sizesmall enough to provide an optically clear solution while contributingto a high refractive index of at least 1.39. In the lens formingenclosure a crosslinking reaction is performed between the units of thesolution in order to form a solid lens, optionally under formingpressure. It is a highly preferred aspect of the present invention thatthe crosslinking reaction between the units is initiated by exposing aphotoinitiator to light of a suitable wavelength and that thephotoinitiator is soluble in the solution and present therein. In thismethod it is preferred that the discrete crosslinkable units aremacromolecular particles having functional groups capable of formingcrosslinks between the particles so as to form the lens. Thecrosslinking reactions preferably are induced by light in the visible orUV spectrum. More preferably, the light has wavelength above 305 nm andmost preferably in the range of 380 to 700 nm.

[0013] The macromolecular particles are preferably prepared fromcontrolled polymerization reaction, as will be explained below ingreater detail, from monomers with suitable characteristics for anophthalmic device, such as being contributory to a product with asuitable refractive index and clinical safety.

[0014] The inventive method can be applied to produce intraocular lenseswith a wide variety of properties both in a conventional mold or, asexplained below, directly in the capsular bag of the eye. Conventionalrigid lenses, semi rigid or flexible foldable lenses can be prepared, aswell as elastically deformable lenses with properties to restore theaccommodation of the patient. For elastically deformable lenses it ishighly preferred that the modulus of the produced lens material iswithin the range of 0.1 to 20 kPa since it can be expected that suchlenses can be accommodated under the influence of the ciliary muscles ofthe eye. It is also a requirement that any lens production in-vivoemploys an aqueous solution for introduction into the capsular bag withso low viscosity that it can be conveniently be injected into the eyewith standard means. In all these applications, it is of considerableadvantage to be able to provide a solution for production whichcomprises crosslinkable units compared to a solution of monomers, sinceit will be possible to overcome any subsequent contraction of thematerial which is a drawback with existing techniques with monomersolutions.

[0015] According to a preferred embodiment, the present invention refersto a method of producing an intraocular lens in vivo, i.e. directly inthe human eye. The method includes the preparation of a composition ofdiscrete water soluble macromolecular particles and mixing such acomposition with a water soluble photoinitiator to an ophthalmicallyacceptable aqueous solution having a refractive index of at least 1.39.The method further includes injection of the resultant aqueous solutioninto the capsular bag of the eye and initiation of crosslinking betweensaid macromolecular particles by irradiation with light of a wavelengthin the range of about 380 to 700 nm to create a lens in the capsularbag.

[0016] It is of particular importance that the inventive methods arrivewith a resultant lens material of a controlled modulus which is similarto the modulus of the natural crystal lens.

[0017] The inventive methods are equally suitable for production of alens in-vivo in the human eye as in molds suitable for conventional lensproduction.

[0018] The present invention also includes an ophthalmically acceptableaqueous solution designed to accomplish the above mentioned inventivemethods.

[0019] It is an important feature of the aqueous solution that itcomprises discrete crosslinkable units of a size small enough to providean optically clear solution. It is a also a requirement that the aqueoussolution has a sufficiently low viscosity to be injected with aconventional cannula into the capsular bag of the eye wherein thenatural lens has been removed with a surgical process. It is a furtherrequirement that the aqueous solution has a sufficiently high refractiveindex so that the resultant lens product has a refractive index of about1.39 to 1.46. Preferably, the lens should have a refractive index ofabout 1.41 to be a suitable replacement of the natural lens. It istherefore desirable that the aqueous solution of crosslinkable units hasa refractive index above about 1.39 already before crosslinking takesplace.

[0020] In order to comply with requirements of optical clarity, lowviscosity and a high refractive index, the aqueous solution of thepresent invention comprises water soluble macromolecular particles of acontrolled size and molecular weight which can undergo crosslinking tothe final product. Suitably, the diameters of the macromolecularparticles are in the range of between about 5 to 160 nm, preferablyabout 10 to 150 nm and more preferably about 20 to 100 nm. Preferably,the molecular weight of the particles are at least 50 000 Daltons.

[0021] Accordingly, it is one of the key features of the invention touse macromolecular particles instead of monomers, or long chains ofconventional polymer molecules, as suggested in prior art, for creatingthe polymeric structure of the lens. By using a solution ofmacromolecular particles, it is possible to obtain a suitably lowviscosity so the solution can be injected by a conventional thincannula, while the solution has a sufficient particle concentration toobtain a high refractive index. To obtain a low viscosity solution withconventional linear polymers would be a considerable technical problemwithout compromising with the polymer concentration and thereby therefractive index of the lens product. Another considerable advantagewith the low viscosity solutions of macromolecular particles accordingto the present invention is their high mobility which for example enableaccurate filling of the lens production enclosure, if necessary byadjustments.

[0022] In order to obtain a suitably high refractive index, it istherefore preferred that the solutions according to the presentinvention comprise at least about 35% (w/w) of the discreetcrosslinkable units (i.e. macromolecular particles and suitably in arange from about 35 to 50% (w/w). If increasing the number units, therefractive index and the viscosity of the solution will accordinglyincrease. It is too be understood that the skilled will be able to finda suitable compromise between these parameters and arrive with solutionssuitable for practicing the inventive methods.

[0023] Further by using macromolecular particles as the basic unit forsubsequent crosslinking, the process in which the final lens is formed,the desired refractive index can be reached by selecting a highconcentration of a suitable monomer contributing to this characteristicwhen forming the particles. The fact that the particles are formed priorto injection outside the eye, also result in a high degree of freedom tochose the best reaction conditions.

[0024] The skilled person can prepare different types of water solublemacromolecular particles for the inventive purposes by followingdifferent preparation routes. It is to be understood that within thecontext of the present invention different types of macromolecularparticles can be prepared with different methods and monomer sources.The most important features of the macromolecular particles are thatthey include units or monomers which contribute to a high refractiveindex and that they include a sufficient amount of functional groups tobe involved in the crosslinking to the final product. Further, theparticles must include a sufficient amount of hydrophilic units ormonomers to obtain suitable water solubility characteristics. Generally,these characteristics can be obtained with various types of particlesincluding microgels or nanogels, dendrimers, nanospheres or particleshaving a core-shell structure such that the shell is hydrophilic and thecore is hydrophobic. The skilled person has the knowledge of numerousdifferent methods to provide such particles including methods ofpreparation in solution and by emulsion polymerization methods.Dependent on the production method and the constituents of the particlea number of methods are also known to the skilled person of how tocollect the particles, purify them and bring them into an aqueoussolution.

[0025] Preferably, the macromolecular particles include at least onehydrophilic group (repeating unit) and at least one group mustcontribute to a high refractive index of the solution of the particles,i.e. such groups preferably consist of a compound which when polymerizedprovides a material of high refractive index. The hydrophilic group andthe high refractive index can be the same or different. Suitablehydrophilic units for the macromolecular particles are found among vinyllactams and acrylamides. Vinyl lactams may generally be defined as avinyl unit bound to a heterocyclic unit through its heterocyclicnitrogen atom, wherein said heterocyclic unit consists of 5 to 7 sevenatoms and has carboxy group neighboring said bond. Some examples ofvinyl lactams are N-vinyl-2-pyrrolidone, N-vinyl-2-piperidone andN-vinyl-caprolactam. Such vinyl lactams may be substituted with one orseveral lower alkyl groups.

[0026] An especially suitable vinyl lactam is N-vinylpyrrolidone and anespecially suitable acrylamide is N,N-dimethylacrylamide. An especiallysuitable group to add as units in the macromolecular particles isN-benzyl-N-methylacrylamide for the purpose of increasing the refractiveindex of the product.

[0027] The macromolecular particles can further comprise a crosslinkingagent which contributes to form crosslinking units in the internalpolymeric network in the particles. An example of such a crosslinkingagent is disclosed below in a specific system where a microgel likecomposition is discussed.

[0028] It is also an important aspect of the present invention that themacromolecular particles comprise units having functional groupssuitable for crosslinking the particles into a solid elasticallydeformable lens. Preferably, the functional groups are selected fromvinylic, acrylic or methacrylic groups.

[0029] The functional groups can be introduced according to differentroutes and chemical design. According to one embodiment the functionalgroups are introduced by means of complementary units in the particlesto the above mentioned hydrophilic units. The functional groups mayeither be directly present on the complementary units or be introducedby further chemical modification of the particles. According to analternative embodiment, the above mentioned crosslinking agent,necessary for creating crosslinking units within the polymeric networkof the particles, can carry a sufficient amount of free functionalgroups for further crosslinking between the particles in order to createthe final lens material.

[0030] One preferred route to introduce the functional groups to theparticles is to add vinylic units to the mentioned hydrophilic units inthe particle network. The vinylic units have groups for attaching thefunctional vinylic, acrylic or methacrylic groups for crosslinkingselected among hydroxy groups, epoxy groups, carboxylic anhydridegroups, lactone groups and isocyanate groups. Vinylic units suitable forthis purpose can be selected from one or several of2-hydroxyethylacrylate, 2-hydroxyethylmethacrylate,2-aminohydroxyethylacrylate, 2-aminoethylacrylate,2-aminoethylmethacrylate, glycidylacrylate and glycidylmethacrylateunits. It is to be understood that the skilled person can find manydifferent alternatives to the exemplified vinylic units with groupssuitable for introducing the mentioned functional groups forcrosslinking.

[0031] According to a preferred embodiment, the vinylic units are vinylalcohol units formed by ester-exchange of vinyl acetate units. The soformed vinyl alcohol units are further chemically modified according tostandard procedures for the introduction of a suitable amount offunctional groups for crosslinking. For a reference of how to introducethis type of functional groups for crosslinking from vinyl acetate as acomonomer of a pre-polymer, it is referred to the aforementioned U.S.Pat. No. 5,665,840.

[0032] An preferred composition of the macromolecular particles is

[0033] a) vinyl lactam and/or acryl amide units;

[0034] b) vinylic units comprising functional groups selected amongvinyl, acrylate and methacrylate groups; and

[0035] c) crosslinking units providing internal crosslinking of theparticles.

[0036] In a typical composition, the macromolecular particles comprise:

[0037] a) N-vinylpyrrolidone and/or N,N-dimethylacrylamide units in anamount of at least 50 w/w %;

[0038] b) vinyl alcohol units having functional groups for crosslinking;and

[0039] c) crosslinking units.

[0040] Furthermore, as complement, the solutions of macromolecularparticles referred to above can also comprise one or several monomerswhich will undergo copolymerization with the macromolecular particleswhen producing the lens material. For this aspect of the invention, thesolution of macromolecular particles can either be aqueous or based onmonomer solution and the photoinitiator must be adapted to be soluble inthe monomer. As mentioned above, it is preferable to employ theinventive method in a mold when the alternative a monomer containingsolution is used. It is also to be understood that the complementarymonomers are selected from agents that contribute to specificallydesired properties of produced lens, such as a suitable refractiveindex.

[0041] Additionally, the solutions referred to comprise furthercomponents necessary for producing lenses, such as UV absorbers,stabilizers and other agents used in common ophthalmologic practice.

[0042] Macromolecular particles can for example be produced with asolution polymerization method as disclosed by N. B Graham et al. inPure & Appl. Chem., 1998, Vol. 70(6), pp. 1271-5 which is herewithincorporated as a reference. For the purposes of the present invention,these methods are modified to prepare water soluble macromolecularparticles of the type of internally crosslinked hydrophilic particles,frequently referred to in the literature as microgels or nanogels. Inthis type of microgels the polymer molecules are constrained by theinternal crosslinks to a spherical structure which prevents chainentanglement, which would otherwise increase the modulus of the formedlens. The precise dimensions of the microgel macromolecular particlesare controlled by the conditions of their preparation and the swellinginduced by the solvent in which they are dissolved. Typically, thediameters of the microgel spheres are in the range 5-160 nm. For thepurposes of the present invention, it is of importance that themacromolecular particles comprise units of at least one hydrophilicgroup and one group with a high refractive index. Monomers having thesecharacteristic must consequently be a substantial part of the startingmaterial for the microgel production. Furthermore a crosslinking agentmust be employed for the internal crosslinking of these particle units.

[0043] Suitable compositions of microgels include at least 50% weight ofhydrophilic monomers and 1 to 50% (weight) of remaining monomerconstituents and crosslinking agents. The remaining monomers referred toare selected according the discussion above regarding additional vinylunits for introducing functional groups for subsequent crosslinking ofthe particles and/or by their capacity to contribute to a highrefractive index. The skilled person would accordingly be able to arrivewith a different compositions given the conditions that particles musthave high overall hydrophilic characteristics, contribute to an aqueoussolution of a high refractive index and a have functional groupsavailable for crosslinking.

[0044] A preferred microgel composition for injection is based onpoly(N-vinylpyrrolidone) and copolymers of polyvinylpyrrolidone with arefractive index above about 1.5.

[0045] Vinylpyrrolidone copolymer microgels (VPCMs) can typically beprepared in a range of compositions by copolymerizing N-vinylpyrrolidone(VP), in mole fractions from 0.95 to 0.50, with vinylacetate (VAc),2-hydroxyethylmethacrylate or another suitable monomer in mole fractionsfrom 0.05 to 0.50, respectively, and a crosslinking monomer (acrosslinker providing internal crosslinking units in the particles),such as, diethylene glycol dimethacrylate, DEGDMA (0.05 moles).α,α′-Azobisisobutyronitrile (in concentrations varying from 0.05 to 3weight-%) can be used as an initiator. Preferably the copolymerizationprocess is heated, using combined monomer concentrations in the range 5to 25 weight-%, in a better than theta solvent at 50 to 80° C. for up to24 hours. In a better than theta solvent the difference in solubilityparameter between the solvent and the polymer is less than about 2MPa^(1/2). For combinations of VP and VAc, solvents of suitablesolubility parameters for the preparation of microgels are formed bymixing acetone and ethanol in molar proportions of acetone: ethanol,from 0.7 to 0.4; 0.3 to 0.6, respectively, which gives solubilityparameters in the range 22 to 23 MPa^(1/2).

[0046] For the subsequent crosslinking to take place in the eye, themicrogel is prepared to contain a controlled amount of active(crosslinkable) sites, e.g. reactive vinyl groups. Since the modulus orrigidity of the lens is directly related to the degree of crosslinkingthe number of such reactive sites per polymer particle is critical formaking accommodating lenses. The degree of crosslinking shouldpreferably be in the range of 0.1 to 1.0, involving volume fractions ofmicrogel from 0.1 to 0.5, based on total composition, i.e. the balancewill derive from water in combination with linear polymers, etc., asrequired to meet the restrictions imposed on concentration by the needto meet a specific refractive index of 1.39 to 1.46.

[0047] In addition to the water soluble crosslinkable macromolecularparticles, the ophthalmically acceptable aqueous solution to be used forintraocular lens production preferably includes a water solublephotoinitiator. The photoinitiator should preferably be capable ofinitiating crosslinking of the particles into a solid elasticallydeformable gel upon exposure of light of a wavelength exceeding about305 nm.

[0048] It is an important object of the present invention that such awater soluble photoinitiator should remain locked into the resultantlens material it contributes to generate. This minimizes anyphysiological hazards from molecular fragments originating from thephotoinitiator regardless of its initial concentration. Therefore, it ispreferable that the photoinitiator residues subsequent to crosslinkingform an integral part of the network constituting the intraocular lensmaterial. In order to accomplish this feature, the photoinitiatorcomprises at least one photoactive compound attached to a water solublemacromolecule. According to a preferred embodiment, the photoinitiatorcomprises photoactive groups attached to linear polymers. Alternatively,the photoinitiator comprises photoactive groups attached tomacromolecular particles. It is to be understood that the macromoleculecarriers of the photoinitiator are compatible with the macromolecularmaterial constituting the particles. Therefore, it is preferred thatthey comprise hydrophilic units such as N-vinyl pyrrolidone, acrylamides and other suitable water solubilizing monomers, such asvinylmorpholine. Photoinitiators of this preferred type can be referredto as photocrosslinkers, since they provide a combination ofphotoinitiating and crosslinking reactions wherein they ultimately forma part of the network forming the resultant material.

[0049] It is suitable that the photoactive group is selected from acyl-and/or aroyl-phosphine oxides. In particular, the photoactive groupcomprises an aroyl group selected from a group consisting of4-carbonylphenylene, 3,5-dimethoxy-4-carbonylphenylene,3,5-dimethylol-4-carbonylphenylene and 3,5-dimethyl-4-carbonylphenylene.Typically preferred photoactive groups are4-vinylbenzoyldiphenylphosphine oxide and4-vinyl-1,6-dimethylbenzoyldiphenyl-phosphine oxide.

[0050] An important feature of the preferred photoinitiators havingphotoactive compounds attached to suitable hydrophilic polymericcarriers is that they have a capacity to, when irradiated by light, actas crosslinkers for the crosslinkable macromolecular particles. Theremaining photoinitiators will thereby form a part of the networkconstituting the lens material or be safely locked within said network.

[0051] It is preferable that the highly reactive ophthalmicallyacceptable aqueous solution is prepared just prior to the injection. Forthis reason the present invention includes the provision of akit-of-parts for preparing the ophthalmically acceptable solutioncomprising a composition of water soluble discrete crosslinkable units,a composition of a water soluble photoinitiator and means for bringingthe compositions together into said aqueous solution for suitablesubsequent injection. It is to be understood that any of the compositionof crosslinkable units or the composition of the photoinitiator may bein dehydrated form during storage for stability reasons and would needreconstitution into an aqueous solution. The kit for preparing the finalaqueous solution can therefore optionally further include a fluid in theform of an aqueous composition for dissolving such a composition andreconstitute it for injection. It is also to be understood that any ofthe compositions of the kit can include additional agents, such asconventional stabilizers or preservatives and agents contributing to thecharacteristics of the final lens product, such as UV-absorbers. It isfurther to be understood that the kit-of-parts can be designed accordingto conventional principles in the pharmaceutical industry and therebyusing conventional methods for protecting the kit from light ofwavelengths that may trigger the reactivity of the photoinitiator. Thepurpose of the design of the kit is that it should be delivered as anarticle which is ready to use for the ophthalmic surgeon. For example,in its simplest form it may comprise different containers with mixinginstruction or it may consist of an injection device capable ofoperating on a multi-chamber ampoule containing the stored precursors tothe ophthalmically acceptable aqueous solution in different chambers.The skilled person is aware of several such suitable devices, see forexample European Patent No. 0298067.

[0052] The methods according to the present invention comprise a meteredintroduction of a high refractive index, low viscosity solution into anenclosure for forming an intraocular lens with subsequent crosslinking,optionally under a forming pressure, wherein the solution comprisescrosslinkable macromolecular particles and a soluble photoinitiator. Themacromolecular particles are chosen so that they after crosslinkingcontribute to reproduce the optical performance of the natural lens,which means a final refractive index close to 1.41, preferably in therange of 1.39 to 1.46.

[0053] Preferably, a high refractive index, low viscosity,ophthalmically acceptable aqueous solution is injected directly into thecapsular bag of the human eye. The lens formed from crosslinking theparticles of the solution, therefore preferably must have the opticaland mechanical characteristics necessary for the restoration ofaccommodation, i.e. the formed lens must be able to accommodate underthe action of the ciliary muscle. The (elasticity) modulus of thematerial of the human crystalline lens has been measured with differenttechniques in different test groups by RF Fisher in J Physiol., 1971,212; pp. 147-180 and G W Alphen et al. in Vision Res., 1991, 31, pp.1417-1438. From these studies it can be concluded that the variations inmodulus of the human lens is within the range of about 0.1 to 20 kPa. Torespond to the accommodating forces the compression characteristics ofthe, resulting lens therefore will have to be precisely controlled andbe very reproducible, with a compressive modulus in the range of fromabout 0.1 to 20 kPa, preferably 0.1 to 10 kPa and most preferably fromabout 1 to 5 kPa.

[0054] By selecting appropriate compositions, as outlined in the presentinvention, it is possible to control the degree of crosslinking in thefinal reaction and thereby control the modulus of the producedintraocular lens. This can for example be accomplished by selectingappropriate materials in the crosslinkable units, by introducing asuitable number of functional groups for crosslinking in thecrosslinkable units or by selecting suitable concentrations of theconstituents of the injectible solution. Accordingly, by means of themethods and the compositions provided by the present invention it ispossible to obtain a high degree of freedom in selecting a suitable lensmodulus for patient and replicate the modulus of a lens in a personaround 40 years or younger.

[0055] The following examples aim to demonstrate a route to perform thepresent invention which is not limited in scope to the specificembodiments disclosed therein.

DETAILED AND EXEMPLIFYING PART OF THE DESCRIPTION

[0056] It has been demonstrated in the British Patent Specification2090264 that the selection of solvent has a critical influence in thepreparation of microgels with respect to their formation and position ofthe gelation boundary. The following examples are illustrative of theproduction of water soluble microgels of differing molecular weights forthe same monomer proportions in different solvents (compare Examples 1and 3) and the use of different monomer combinations (compare Examples 2and 4).

EXAMPLE 1

[0057] Vinylacetate (VAc) (10 w/w %, 0.20 g, 2.3 mmol),diethylene-glycol divinylether (DEGDVE) (5 w/w %, 0.10 g, 0.63 mmol),N-vinylpyrrolidone (NVP) (85 w/w %, 1.7 g, 15.3 mmol) were dissolved inmethanol (3.71 g, 4.69 ml) to give 35 w/w % solution. The solution waspoured into a Wheaton serum bottle and azo-isobutyronitrile (AIBN, 0.060g, 3 w/w % of total monomers) was added. The bottle was sealed, shakenfor 2 min. and placed in an oven at 60° C. and the reaction mixture washeated for 24 hours. Upon cooling the solution from the reaction, theresulting microgel was precipitated with ether, collected by filtrationand dried in a vacuum oven at room temperature. The yield was 1.92 g(96%) and colorless microgel particles were soluble in water, ethanoland methanol. The weight average molar mass (M_(w)) of this product,when curve fitted and averaged was 280 000 D. M_(w) was measured bySEC/MALS (size exclusion chromatography with multi-angel lightscattering).

EXAMPLE 2

[0058] The preparative method described in Example 1 was repeated in 50w/w % solution of ethanol (2.00 g, 2.52 ml) instead of methanol 35 w/w%. The product was worked up as described previously in Example 1 andthe yield was 1.85 g (about 93%) of colorless microgel particles whichwere soluble in water, ethanol and methanol. The weight average molarmass (M_(w)) of this product, when curve fitted and averaged was 500 000D. Mw was measured by SEC/MALS.

EXAMPLE 3

[0059] The preparative method described in Example 1 was repeated in 50w/w % solution of butane-2-one (2.00 g, 4.48 ml) instead of methanol 35w/w %. The product was worked up as described previously in Example 1and the yield was 1.90 g (95%) of having a bimodal weight average molarmass (Mw), when curve fitted and averaged, a first peak of 25 200 D anda second peak of 5 257 000 D were identified. Mw:s were measured bySEC/MALS.

EXAMPLE 4

[0060] N,N-dimethylacrylamide (DMA), (6.40 g, 57 mmol), 2-hydroxyethylmethacrylate (HEMA), (0.80 g, 6.2 mmol) and ethyleneglycoldimethacrylate (EGDMA), (0.80 g, 4.0 mmol) were weighed to a pressureflask, AIBN (azo-bisisobutyronitrile) (0.20 g, 0.25 w/w monomers %) intoethanol was added, and the volume made up to 100 ml with ethanol(monomer concentration 8 w/v %). The flask was flushed with N₂, andheated at 60° C. for 24 h. The product from the reaction wasprecipitated with hexane, the precipitate dissolved in tetrahydrofuran,reprecipitated with ether and vacuum desiccated to constituent weight.The yield 5.46 g (68%) of white microgel particles which were soluble inwater, alcohol, tetrahydrofuran, and chloroform. SEC-MALS showed a Mw ofthis microgel (using a curve-fitted average) to be 2.69×10⁶ D and theaverage particle diameter to be 70 run. A 35 w/w % (38 w/v %) solutionof the microgel in water was a colorless liquid with refractive index1.395 and viscosity 730 cSt, both measured at 25° C. H-NMR analysissuggested that DMA, HEMA and EGDMA had entered the polymer in close tostoichiometric ratio.

EXAMPLE 5

[0061] Using the method described in Example 4 with DMA (7.20 g, 64mmol), HEMA (1.08 g, 8.3 mmol), EGDMA (0.72 g, 3.6 mmol) and AIBN (0.023g, 0.26 w/w monomers %) dissolved in ethanol to give a 9 w monomers/v %solution. The product was microgel (5.71 g, 63% yield), having a M_(w)of 2.47×10⁵ D, and an average particle diameter of 144 nm (both bySEC/MALS analysis, as previously). This product was soluble in water andsome other common solvents giving mobile colorless solutions.

EXAMPLE 6

[0062] Using the method described in Example 4 with DMA (7.20 g, 64mmol), HEMA (0.99 g, 7.6 mmol), EGDMA (0.81 g, 4.1 mmol) and AIBN (0.023g, 0.26 w/w monomers %) dissolved in ethanol to give a 9 W monomers/v %solution. The product was microgel (5.12 g, 57% yield), having a Mw of2.68×10⁷ D, and an average particle diameter of 138 nm (both by SEC/MALSanalysis, as previously). This product was soluble in water and someother common solvents giving mobile colorless solutions.

EXAMPLE 7

[0063] A mixture of the monomers was prepared: 75 partsN,N-dimethylacrylamide (DMA), 10 parts N-benzyl-N-methylacrylamide,(BMA), 5 parts 2-hydroxyethyl methacrylate (HEMA), and 10 partsethyleneglycol dimethacrylate (EGDMA), by weight, and 2.8 g of themixture was placed in a 50 ml penicillin bottle.Azo-bisisobutyronitrile, 7 mg in ethanolic solution, was added, and thevolume made up to 35 ml with ethanol, thus 8 w/v % monomers. The vesselwas purged with nitrogen, septum sealed, and heated 22 h at 60° C.,after which the clear solution was poured to ether, and the productreprecipitated from ethanol. The vacuum dried yield was 1.06 g (38%) ofwhite polymer. H-NMR analysis showed a molar ratio: 7.4/92;6 BMA/DMA.The refractive index of a 35 w/w % solution was 1.396 at 25° C.

EXAMPLE 8

[0064] Modification of NVP/VAc Microgel by Ester Exchange.

[0065] Microgel (10 g), containing VAc units (12.5 mmol) prepared in amanner similar to Example 1, was dissolved in methanol (100 ml) and tothe resulting solution was added a solution of sodium hydroxide (0.36 g,9 mmol) in water (3 ml). The microgel solution was stirred and heated at40° C. for 24 h. The resulting solution of modified microgel wasdialyzed versus water for 48 h and the methanol and water were removedby evaporation in a rotary evaporator at ambient temperature and driedthoroughly in a vacuum oven at 40° C. The IR spectrum of the recoveredmicrogel indicated that the conversion of acetate to hydroxyl groups wasabout 90%.

EXAMPLE 9

[0066] Using microgel (10 g, approximately 12.5 mmol VAc repeatingunits) prepared in a manner similar to Example 2, the ester-exchangereaction described in Example 8 was repeated. IR analysis revealed thatthe product was again about 90% converted (acetate to alcohol).

EXAMPLE 10

[0067] Further Modification of NVP/VAc Microgel Introducing Vinyl GroupsServing as Functional Groups for Crosslinking Between the Particles.

[0068] Microgel product from Example 9 (5.0 g, containing approximately11 mmol of vinyl alcohol units) was dissolved in dimethylacetamide(DMAc, 45 ml) and triethylamine (TEA, 0.81 g, 8.1 mmol) was added to thesolution while stirring. Methacroyl chloride (MACl, 1.1 g, 10.5 mmol)was next added very slowly, dropwise, with continued stirring at roomtemperature. Stirring of the reaction mixture was continued for afurther 24 h at 40° C. in the dark.

[0069] The reaction solution was diluted with DMAc (50 ml) and pouredinto an excess of acetone (1.5 l) to precipitate the vinylated microgel.This was collected at the pump, washed thoroughly with acetone and driedin vacuo at room temperature. The NMR spectrum indicated 3-5 mol % vinylgroups.

EXAMPLE 11

[0070] Microgel prepared in accordance with Example 4 (6.01 g) wasdissolved in 58 ml DMAc and treated as in Example 10. Acryloyl chloride(2.03 g) was added and mixture and resulting product was treated as inExample 10 with a yield of 5.20 g. NMR analysis showed vinyl peaks inmolar ratio of 0.10/0.90 acryl groups/DMA units.

EXAMPLE 12

[0071] Microgel product from Example 4 (5.0 g) was weighed to a adriedflask and dissolved in N,N-dimethylacetamide 48 ml. Methacroyl chloride(MACl, 2.05 g) was added and the mixture heated in a bath at 40° C. for18 h. the clear colorless solution resulting was poured into hexane, andthe product taken up in absolute alcohol and reprecitated to diethylether, before drying under vacuum at room temperature. The yield was4.13 g of white polymer. In aqueous solution, the product decolorizedbromine water. H-NMR analysis showed polymeric vinyl peaks (d 6.13 and5.60 ppm) in molar ratio 0.11/0.89 methacryl groups/DMA units.

EXAMPLE 13

[0072] The viscosity and refractive index were tested herein forconcentrated solutions of microgels suitable for preparation ofophthalmically acceptable aqueous liquids for lens production. Theapplication of microgel systems to the molding an of an artificialcrystalline lens (ACL) requires the injection of a concentrated aqueous(saline) solution of the microgel through a standard cannula into thecapsular bag of the eye. The Table below gives examples that illustratethat aqueous microgel solutions have suitable viscosities and refractiveindices (selected) for ACL applications. Refractive Microgel ViscosityInjection thro' 18 Index Composition (w/w %) (cSt) gauge cannula (Y/N)(w/H20 v %) NVP(55)/VAc(40)/ 180-250 Y 1.39(33) DEGDVE(5)NVP(90)/VAc(5)/ <180 Y 1.39(31) DEGDVE(5) DMA(80)/HEMA(10)/   730 Y1.395(38) EGDMA(10)

EXAMPLE 14

[0073] 0.300 g Microgel modified with functional vinyl groups forcrosslinking in accordance with Example 11 was weighed into a vial and0.704 g water was added. On standing, the microgel was dissolved to aclear colorless solution. A photoinitiator for starting the crosslinkingwas added to the solution (0.102 g) and the mixture was warmed todissolve.

[0074] The photoinitiator comprises a photoactive linear polymer of acopolymer of N.N-dimethylacrylamide containing 2.0 mol % of photoactiveunits derived from 1,6-dimethylbenzoylphosphine oxide. An aliquot of themixture was easily dispensed through 18 gauge needle to a Teflon diskand covered with a glass slide. On 2 minutes irradiation with blue light(source: Vivadent Heliolux DLX dental gun emitting 400-525 nm), themixture formed a tack-free gel.

EXAMPLE 15

[0075] Microgel prepared according to Example 11, was dissolved in waterto give a 35 w/w % solution. An aliquot of this solution, 358 mg, wasmixed with 58 mg of a 25 w/w % solution of the same photoinitiator as inExample 11 and 175 mg of the mixture was transferred through an 18 gaugehypodermic cannula to a Teflon disk. On irradiating with blue light(source: Vivadent Heliolux DLX dental gun, emitting 400-525 nm) for 20seconds, a transparent gel with elastic properties was formed.

1. A method of producing an intraocular lens including: (i) introducinga solution into a lens forming enclosure, said solution comprisingdiscrete crosslinkable units of a size small enough to provide anoptically clear solution while contributing to a high refractive indexof at least 1.39; (ii) performing crosslinking between said units of thesolution; and thereby (iii) forming a solid lens in said enclosure,optionally under a forming pressure.
 2. A method according to claim 1wherein said crosslinking is initiated exposing a photoinitiator whichis soluble in said solution to light.
 3. A method according to claim 2,wherein said crosslinkable units are macromolecular particles having asize range between about 20 to 160 nm.
 4. A method according claim 2,wherein said solution has a sufficiently low viscosity to be injectedwith a conventional cannula into said forming enclosure.
 5. A methodaccording to claim 4, wherein the forming enclosure is the capsular bagof the eye where the natural lens has been removed with a surgicalprocess.
 6. A method according to claim 5, wherein formed lens is anelastically deformable lens with a modulus in the range of about 0.1 to20 kPa.
 7. A method according to claim 6, wherein the resulting lensformed in the capsular bag has the optical and mechanicalcharacteristics necessary for the restoration of accommodation.
 8. Amethod according to claim 2, wherein said crosslinking reaction isinitiated by light of a wavelength above about 305 nm.
 9. A methodaccording to claim 4, wherein said solution is an ophthalmicallyacceptable aqueous solution.
 10. A method according to claim 9 whereinthe aqueous solution comprises a water soluble photoinitiator.
 11. Amethod according to claim 10, wherein the soluble photoinitiatorcomprises at least on photoactive compound attached to a water solublemacromolecule.
 12. A method according to claim 3, wherein saidmacromolecular particles are provided with functional groups forcrosslinking.
 13. A method according to claim 12, wherein the functionalgroups are selected among vinylic, acrylic or methacrylic groups.
 14. Amethod according to claim 12, wherein the macromolecular particles arewater soluble.
 15. A method according to claim 14, wherein themacromolecular particles comprise units selected among vinyl lactams andacrylamides of which at least one contribute to provide a solution ofthe particles with a refractive index of at least 1.39 and at least onecontribute to provide the particles with hydrophilic overallcharacteristics.
 16. A method of producing an intraocular lens in vivo,comprising the steps of: (i) preparing a composition of discrete watersoluble macromolecular particles; (ii) mixing said composition with awater soluble photoinitiator and forming an ophthalmically acceptableaqueous solution having a refractive index of at least 1.39; (iii)injecting the resultant aqueous solution into the capsular bag of theeye; and (iv) initiating crosslinking between said macromolecularparticles by irradiation with light of a wavelength in the range ofabout 380 to 700 nm to create a lens in the capsular bag.
 17. A methodaccording to claim 16, wherein the macromolecular particles compriseunits of at least one hydrophilic group and at least one group giving ahigh refractive index.
 18. A method according to claim 17, wherein saidhydrophilic group is a vinyl lactam or an acrylamide.
 19. A methodaccording to claim 18, wherein said vinyl lactam is N-vinylpyrrolidone.20. A method according to claim 17, wherein said hydrophilic group isN,N-dimethylacrylamide.
 21. A method according to claim 16, wherein themacromolecular particles comprise a crosslinking agent.
 22. A methodaccording to claim 17, wherein the macromolecular particles furthercomprise units having functional groups suitable for crosslinking theparticles into a solid elastically deformable lens, said groups beingselected from vinylic, acrylic and methacrylic groups.
 23. A methodaccording to claim 22, wherein said units are vinyl alcohol units formedby ester-exchange of vinyl acetate units.
 24. A method according toclaim 22, wherein said functional groups are introduced by attachment tovinylic units of the macromolecular particles.
 25. A method according toclaim 24, wherein said vinylic units have groups for attaching thefunctional groups for crosslinking selected among hydroxy groups, epoxygroups, carboxylic anhydride groups, lactone groups and isocyanategroups.
 26. A method according to claim 24, wherein said vinylic unitsare selected from a group consisting of 2-hydroxyethylacrylate,2-hydroxyethylmethacrylate, 2-aminohydroxyethylacrylate,2-aminoethylacrylate, 2-aminoethylmethacrylate, glycidylacrylate andglycidylmethacrylate units.
 27. A method according to claim 17, whereinthe macromolecular particles comprise: a) vinyl lactam units and/oracrylamide units b) vinylic units comprising functional groups selectedamong vinyl, acrylate and methacrylate groups; and c) a crosslinkingagent.
 28. A method according to claim 16, wherein the water solublephotoinitiator comprises photoactive groups attached to linear polymers.29. A method according to claim 16, wherein the water solublephotoinitiator comprises photoactive groups attached to macromolecularparticles.
 30. A method according claim 28 or 29, wherein thephotoactive group is selected from acyl- and/or aroyl-phosphine oxides.31. A method according to claim 29, wherein the photoactive groupcomprises an aroyl group selected from a group consisting of4-carbonylphenylene, 3,5-dimethoxy-4-carbonylphenylene,3,5-dimethylol-4-carbonylphenylene and 3,5-dimethyl-4-carbonylphenylene.32. A method according to claim 31, wherein the photoactive group is a4-vinylbenzoyldiphenylphosphine oxide.
 33. A method according to claim28 or 29, wherein the photoinitiator when irradiated by light acts as acrosslinker for the crosslinkable macromolecular particles.
 34. A methodaccording to claim 28 or 29, wherein the photoinitiator residuessubsequent to crosslinking form an integral part of the networkconstituting the intraocular lens material.
 35. An ophthalmicallyacceptable aqueous solution suitable for producing intraocular lensesaccording to any of the methods according to claims 1 to 34 comprisingdiscrete crosslinkable units of a size small enough to provide anoptically clear solution.
 36. An aqueous solution according to claim 35,wherein the discrete units are water soluble macromolecular particles.37. An aqueous solution according to claim 35 having a sufficiently lowviscosity to be injected into a closed site for lens production with aconventional cannula.
 38. An aqueous solution according to claim 35having a refractive index of at least 1.39.
 39. An aqueous solutionaccording to claim 36, wherein said macromolecular particles areprovided with functional groups for a crosslinking reaction.
 40. Anaqueous solution according to claim 39, wherein said functional groupsare reactive vinyl, acrylic or methacrylic groups.
 41. An aqueoussolution according to claim 36, wherein the macromolecular particlescomprise at least one hydrophilic unit and at least one unitcontributing to a high refractive index of the solution.
 42. An aqueoussolution according to claim 36, wherein the macromolecular particleshave molecular weights of at least 50 000 Daltons and a diameters in therange of about 5 to 160 nm.
 43. An aqueous solution according to claim41, wherein the hydrophilic unit is selected among vinyl lactams andacrylamides.
 44. An aqueous solution according to claim 41, wherein thehydrophilic unit is N-vinylpyrrolidone or N,N-dimethylacrylamide.
 45. Anaqueous solution according to claim 41 further comprising vinylic unitsto which said functional groups for crosslinking are attached.
 46. Anaqueous solution according to claim 45, wherein said vinylic units arevinyl alcohol units.
 47. An aqueous solution according to claim 45,wherein said vinylic units are selected among 2-hydroxyethylacrylate,2-hydroxyethylmethacrylate, 2-aminohydroxyethylacrylate,2-aminoethylacrylate, 2-aminoethylmethacrylate, glycidylacrylate andglycidylmethacrylate units.
 48. An aqueous solution according to claim41, wherein the macromolecular particles comprise a crosslinking agent.49. An aqueous solution according to claim 35, comprising a watersoluble photoinitiator which is capable of crosslinking said units to asolid elastically deformable gel upon exposure of light of a wavelengthexceeding about 305 nm.
 50. An aqueous solution according to claim 49,wherein the water soluble photoinitiator comprises photoactive groupsattached to linear polymers.
 51. An aqueous solution according to claim49, wherein the water soluble photoinitiator comprises photoactivegroups attached to macromolecular particles.
 52. An aqueous solutionaccording to claim 50 or 51, wherein the photoactive group is selectedfrom acyl- and/or aroyl-phosphine oxides.
 53. An aqueous solutionaccording to claim 52, wherein the photoactive group comprises an aroylgroup selected from a group consisting of 4-carbonylphenylene,3,5-dimethoxy-4-carbonylphenylene, 3,5-dimethylol-4-carbonylphenyleneand 3,5-dimethyl-4-carbonylphenylene.
 54. An aqueous solution accordingto claim 53, wherein the photoactive group is4-vinylbenzoyldiphenylphosphine oxide.
 55. An aqueous solution accordingto claim 50 or 51, wherein the photoinitiator when irradiated by lightacts as a crosslinker for the crosslinkable macromolecular particles.56. An aqueous solution according to claim 50 or 51, wherein thephotoinitiator residues subsequent to crosslinking form an integral partof the network constituting the intraocular lens material.
 57. Akit-of-parts for preparing the ophthalmically acceptable solutionaccording to any of claims 35 to 56 just prior to injection into thelens production site comprising a composition of water soluble discretecrosslinkable units, a composition of a water soluble photoinitiator andmeans for bringing the compositions together into said aqueous solutionfor suitable subsequent injection.
 58. A kit-of-parts according to claim57 further comprising an ophthalmically acceptable aqueous composition.